Excessive alcohol consumption is a major threat to human health. Normal host defense mechanisms are compromised in alcoholic patients, often resulting in pronounced frequency and severity of infections. Both clinical and experimental evidence suggest that alcohol alters the immune system. Chronic alcohol consumption impairs induction of human cell- mediated immune responses and elevates serum antibody levels. A mouse model employing synthetic copolymer antigens shows that ethanol enhances poly(Glu/50Tyr/50) (GT)-specific humoral immunity and impairs poly(Glu/60Ala/30Tyr/10)(GAT)-specific cell-mediated immunity regulated by CD-4 bearing helper (Th) lymphocytes designated Th2 and Th1, respectively. Despite its impact upon defense, little is known of how ethanol alters immune function. Other agents which alter immune function, such as cyclophosphamide and gamma-irradiation, provide a common thread with ethanol in that all deplete the intracellular thiols cysteine and glutathione (GSH). T cells have extremely weak cystine transport activity and cannot make cysteine. T cell function is exquisitely sensitive to intracellular GSH depletion. Intracellular thiols inhibit the activation of nuclear factor-kappaB (NF-kappaB), a T cell transcription factor, a factor that also controls replication of human immunodeficiency virus (HIV). Chronic ethanol consumption may increase susceptibility to HIV infection for those individuals at risk. Clinically, N-acetyl-L-cysteine (NAC) is administered to replenish GSH levels. Both cysteine and NAC inhibit the activation of NF-kappaB and also inhibit the replication of HIV which is under transcriptional control of NF-kappaB. Our preliminary findings show that oral administration of NAC restores GAT-specific cell- mediated immune function delayed hypersensitivity) to ethanol-consuming C57BL/6 mice and causes a marked decrease in serum alcohol concentrations. We propose to direct the activities of our laboratory toward three major goals; 1) The effect of glutathione replenishment using NAC and related compounds on cell-mediated (GAT) and humoral immune (GT) responses in ethanol-consuming mice. 2) Identify which cells of the immune system, lymphocytes or macrophages, are most affected by glutathione depletion/repletion. 3) Identify how cells of the immune system are affected (e.g., antigen presentation, signal transduction, lymphokine production) when depleted of GSH by ethanol and when glutathione is replenished. This exciting finding may lend significant insights into the mechanism(s) of immune alteration by ethanol and may offer strategies to minimize risk to alcoholics of HIV infection and other infectious organisms.